Many hormones and neurotransmitters modulate tissue function by elevating intracellular levels of adenosine 3', 5'-cyclic monophosphate (cAMP). The cellular levels of cAMP are regulated by mechanisms which control synthesis and breakdown. The synthesis of cAMP is controlled by adenylyl cyclase which may be directly activated by agents such as forskolin or indirectly activated by the binding of specific agonists to cell surface receptors which are coupled to adenylyl cyclase. The breakdown of cAMP is controlled by a family of phosphodiesterase (PDE) isoenzymes, which also control the breakdown of guanosine 3',5'-cyclic monophosphate (cGMP). To date, seven members of the family have been described (PDE I-VI1) the distribution of which varies from tissue to tissue. This suggests that specific inhibitors of PDE isoenzymes could achieve differential elevation of cAMP in different tissues, [for reviews of PDE distribution, structure, function and regulation, see Beavo & Reifsnyder (1990) TIPS, 11: 150-155 and Nicholson et al (1991) TIPS, 12: 19-27].
There is clear evidence that elevation of cAMP in inflammatory leukocytes leads to inhibition of their activation. Furthermore, elevation of cAMP in airway smooth muscle has a spasmolytic effect. In these tissues, PDE IV plays a major role in the hydrolysis of cAMP. It can be expected, therefore, that selective inhibitors of PDE IV would have therapeutic effects in inflammatory diseases such as asthma, by achieving both anti-inflammatory and bronchodilator effects.
The design of PDE IV inhibitors has met with limited success to date, in that many of the potential PDE IV inhibitors which have been synthesized have lacked potency and/or have been capable of inhibiting more than one type of PDE isoenzyme in a nonselective manner. Lack of selective action has been a particular problem given the widespread role of cAMP in vivo and what is needed are potent selective PDE IV inhibitors with an inhibitory action against PDE IV and little or no action against other PDE isoenzymes.
We have now found a novel series of tri-substituted phenyl derivatives, members of which compared to known structurally similar compounds are potent inhibitors of PDE IV at concentrations at which they have little or no inhibitory action on other PDE isoenzymes. These compounds inhibit the isolated PDE IV enzyme and also elevate cAMP in isolated leukocytes. Certain compounds prevent inflammation in the lungs induced by carrageenan, platelet-activating factor (PAF), interleukin-5 (IL-5) or antigen challenge. These compounds also suppress the hyperresponsiveness of airway smooth muscle seen in inflamed lungs. Advantageously, compounds according to the invention have good oral activity and at orally effective doses exhibit little or none of the side-effects associated with known PDE IV inhibitors, such as rolipram. The compounds of the invention are therefore useful in medicine, especially in the prophylaxis and treatment of asthma.
Thus, according to one aspect of the invention, there is provided a compound of formula (1) ##STR2## wherein Y is halogen or --OR.sup.1, where R.sup.1 is substituted or unsubstituted alkyl;
X is --O--, --S-- or --N(R.sup.8)--, where R.sup.8 is hydrogen or alkyl; PA1 R.sup.2 is substituted or unsubstituted alkyl, alkenyl, cycloalkyl or cycloalkenyl; PA1 R.sup.3 is hydrogen, halogen or --OR.sup.9, where R.sup.9 is hydrogen or substituted or unsubstituted alkyl, alkenyl, alkoxyalkyl or alkanoyl, or formyl, carboxamido or thiocarboxamido; PA1 R.sup.4 and R.sup.5, which may be the same or different, is each independently --(CH.sub.2).sub.n Ar, where Ar is substituted or unsubstituted, monocyclic or bicyclic aryl or substituted or unsubstituted, monocyclic or bicyclic heteroaryl, wherein said heteroatom is oxygen, sulphur or nitrogen and n is an integer of 0 to 3; PA1 R.sup.6 is hydrogen or substituted or unsubstituted alkyl; and PA1 R.sup.7 is hydrogen or substituted or unsubstituted alkyl; and the salts, solvates, hydrates and N-oxides thereof.
It will be appreciated that the compounds of formula (1) may have one or more chiral centers, depending on the nature of the groups R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7. Where one or more chiral centers is present, enantiomers or diastereomers may exist, and the invention is to be understood to extend to all such enantiomers, diastereomers and mixtures thereof, including racemates.
In the compounds of formula (1), when Y is halogen, it may be, for example, fluorine, chlorine, bromine or iodine.
When Y in the compounds of formula (1) is --OR.sup.1, R.sup.1 may be, for example, substituted or unsubstituted, straight or branched alkyl, including, for example, C.sub.1-6 alkyl, such as methyl, ethyl, n-propyl or i-propyl. Optional substituents which may be present on the R.sup.1 groups include one or more halogen atoms, for example, fluorine, or chlorine atoms. Exemplary substituted alkyl groups include, for example, --CH.sub.2 F, --CH.sub.2 Cl, --CHF.sub.2, --CHCl.sub.2, --CF.sub.3 and --CCl.sub.3 groups.
Alkyl groups represented by R.sup.2, R.sup.6 or R.sup.7 in the compounds of formula (1) include substituted or unsubstituted, straight or branched C.sub.1-6 alkyl, including, for example, C.sub.1-3 alkyl, such as methyl or ethyl. Optional substituents on these alkyl groups include one, two or three substituents selected from halogen, for example, fluorine, chlorine, bromine or iodine, hydroxyl or C.sub.1-6 alkoxy, for example, C.sub.1-3 alkoxy, such as methoxy or ethoxy.
Alkenyl groups represented by R.sup.2 in the compounds of formula (1) include substituted or unsubstituted, straight or branched C.sub.2-6 alkenyl, such as ethenyl, propen-1-yl and 2-methylpropen-1-yl. Optional substituents include those described above in connection with R.sup.2, R.sup.6 and R.sup.7.
When R.sup.2 in the compounds of formula (1) is substituted or unsubstituted cycloalkyl or cycloalkenyl, it may be, for example C.sub.3-8 cycloalkyl, such as cyclobutyl, cyclopentyl or cyclohexyl, or C.sub.3-8 cycloalkenyl containing, for example, one or two double bonds, such as 2-cyclobuten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2,4-cyclopentadien-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 2,4-cyclohexadien-1-yl or 3,5-cyclohexadien-1-yl, each cycloalkyl or cycloalkenyl group being optionally substituted by one, two or three substituents selected from halogen, for example, fluorine, chlorine, bromine or iodine, straight or branched C.sub.1-6 alkyl, for example, C.sub.1-3 alkyl, such as methyl or ethyl, hydroxyl or C.sub.1-6 alkoxy, for example, C.sub.1-3 alkoxy, such as methoxy or ethoxy.
Alkyl groups represented by R.sup.8 in the compounds of formula (1) include straight or branched C.sub.1-6 alkyl, for example, C.sub.1-3 alkyl, such as methyl or ethyl. When R.sup.3 in the compounds of formula (1) is halogen, it may be, for example, fluorine, chlorine, bromine or iodine.
When R.sup.3 in the compounds of formula (1) is --OR.sup.9, it may be, for example, hydroxyl or --OR.sup.9, where R.sup.9 is substituted or unsubstituted, straight or branched C.sub.1-6 alkyl, for example, C.sub.1-3 alkyl, such as methyl or ethyl, C.sub.2-6 alkenyl, such as ethenyl or 2-propen-1-yl, C.sub.1-3 alkoxyC.sub.1-3 alkyl, such as methoxymethyl, ethoxymethyl or ethoxyethyl, C.sub.1-6 alkanoyl, for example, C.sub.1-3 alkanoyl, such as acetyl, or formyl [HC(.dbd.O)--], carboxamido (--CONR.sup.11 R.sup.12) or thiocarboxamido (--CSNR.sup.11 R.sup.12), where R.sup.11 and R.sup.12 in each instance may be the same or different and is each independently hydrogen or substituted or unsubstituted, straight or branched C.sub.1-6 alkyl, for example, C.sub.1-3 alkyl, such as methyl or ethyl. Optional substituents which may be present on R.sup.9 include those described above in connection with the alkyl groups R.sup.2, R.sup.6 and R.sup.7.
In the compounds of formula (1), R.sup.4 and R.sup.5 may each independently be --Ar, --CH.sub.2 Ar, --(CH.sub.2).sub.2 Ar or --(CH.sub.2).sub.3 Ar.
Monocyclic or bicyclic aryl groups represented by Ar in the compounds of formula (1) include, for example, substituted or unsubstituted C.sub.6-12 aryl, for example substituted or unsubstituted phenyl, 1- or 2-naphthyl, indenyl or isoindenyl.
When the monocyclic or bicyclic aryl group Ar contains one or more heteroatoms, it may be, for example, substituted or unsubstituted C.sub.1-9 heteroaryl containing, for example, one, two, three or four heteroatoms selected from oxygen, sulphur and nitrogen atoms. In general, Ar heteroaryl groups may be, for example, substituted or unsubstituted, monocyclic or bicyclic heteroaryl groups. Monocyclic heteroaryl groups include, for example, five- or six-membered heteroaryl groups containing one, two, three or four heteroatoms selected from oxygen, sulphur and nitrogen atoms.
Examples of heteroaryl groups represented by Ar include pyrrolyl, furyl, thienyl, imidazolyl, N-methylimidazolyl, N-ethylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, benzofuryl, isobenzofuryl, benzothienyl, isobenzothienyl, indolyl, isoindolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, naphthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl, quinolinyl, isoquinolinyl, tetrazolyl, 5,6,7,8-tetrahydroquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl.
The heteroaryl group represented by Ar may be attached to the remainder of the molecule of formula (1) through any ring carbon or heteroatom, as appropriate. Thus, for example, when Ar is pyridyl, it may be 2-pyridyl, 3-pyridyl or 4-pyridyl. When it is thienyl, it may be 2-thienyl or 3-thienyl, and, similarly, when it is furyl, it may be 2-furyl or 3-furyl.
When, in the compounds of formula (1), Ar is a nitrogen-containing heterocycle, it may be possible to form quaternary salts, for example, N-alkyl quaternary salts, and the invention is to be understood to extend to such salts. Thus, for example, when Ar is pyridyl, pyridinium salts may be formed, for example N-alkylpyridinium salts, such as N-methylpyridinium.
The aryl or heteroaryl groups represented by Ar in the compounds of formula (1) may each optionally be substituted by one, two, three or more substituents [R.sup.10 ]. The substituent R.sup.10 may be R.sup.13 or --Alk.sup.1 (R.sup.13).sub.m, wherein R.sup.13 is halogen, amino (--NH.sub.2), substituted amino, nitro, cyano, hydroxyl (--OH), substituted hydroxyl, cycloalkoxy, formyl [HC(.dbd.O)--], carboxyl (--CO.sub.2 H), esterified carboxyl, thiol (--SH), substituted thiol, --COAlk.sup.1, --SO.sub.3 H, --SO.sub.2 Alk.sup.1, --SO.sub.2 NH.sub.2, --SO.sub.2 NHAlk.sup.1, --SO.sub.2 N[Alk.sup.1 ].sub.2, --CONH.sub.2, --CONHAlk.sup.1, --CON[Alk.sup.1 ].sub.2, --NHSO.sub.2 H, --NHSO.sub.2 Alk.sup.1, --N[SO.sub.2 Alk.sup.1 ].sub.2, --NHSO.sub.2 NH.sub.2, --NHSO.sub.2 NHAlk.sup.1, --NHSO.sub.2 N[Alk.sup.1 ].sub.2, --NHC(O)Alk.sup.1, or --NHC(O)OAlk.sup.1 ; Alk.sup.1 is straight or branched C.sub.1-6 alkylene, C.sub.2-6 alkenylene, or C.sub.2-6 alkynylene chain, optionally interrupted by one, two, or three --O-- or --S-- atoms, --S(O).sub.p -- [where p is 1 or 2] or --N(R.sup.8)--; and m is an integer of 0 to 3.
When m in --Alk.sup.1 (R.sup.13).sub.m is 1, 2 or 3, it is to be understood that the substituent or substituents R.sup.13 may be present on any suitable carbon atom in --Alk.sup.1. Where more than one R.sup.13 substituent is present, they may be the same or different and may be present on the same carbon atom or on different carbon atoms in Alk.sup.1. Clearly, when m is zero and no substituent R.sup.13 is present, or when Alk.sup.1 forms pan of, for example, --SO.sub.2 Alk.sup.1, the alkylene, alkenylene or alkynylene chain represented by Alk.sup.1 becomes alkyl, alkenyl or alkynyl.
When R.sup.13 is substituted amino, it may be --NHAlk.sup.1 (R.sup.13a).sub.m [where Alk.sup.1 and m are as defined above and R.sup.13a has the same definition as R.sup.13 but is not substituted amino, substituted hydroxyl or substituted thiol] or --N[Alk.sup.1 (R.sup.13a).sub.m ].sub.2, wherein each --Alk.sup.1 (R.sup.13a).sub.m is the same or different.
When R.sup.13 is halogen, it may be, for example, fluorine, chlorine, bromine, or iodine.
When R.sup.13 is cycloalkoxy, it may be, for example, C.sub.5-7 cycloalkoxy, such as cyclopentyloxy or cyclohexyloxy.
When R.sup.13 is substituted hydroxyl or substituted thiol, it may be --OAlk.sup.1 (R.sup.13a).sub.m or --SAlk.sup.1 (R.sup.13a).sub.m, respectively, where Alk.sup.1, R.sup.13a and m are as defined above.
Esterified carboxyl groups represented by R.sup.13 include, for example, --CO.sub.2 Alk.sup.2, wherein Alk.sup.2 is substituted or unsubstituted, straight or branched C.sub.1-8 alkyl, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl; substituted or unsubstituted C.sub.6-12 arylC.sub.1-8 alkyl, such as benzyl, phenylethyl, phenylpropyl, 1naphthylmethyl or 2-naphthylmethyl; substituted or unsubstituted C.sub.6-12 aryl, such as phenyl, 1-naphthyl or 2-naphthyl; substituted or unsubstituted C.sub.6-12 aryloxyC.sub.1-8 alkyl, such as phenyloxymethyl, phenyloxyethyl, 1-naphthyloxymethyl or 2-naphthyloxymethyl; substituted or unsubstituted C.sub.1-8 alkanoyloxyC.sub.1-8 alkyl, such as pivaloyloxymethyl, propionyloxyethyl or propionyloxypropyl; or substituted or unsubstituted C.sub.6-12 aroyloxyC.sub.1-8 alkyl, such as benzoyloxyethyl or benzoyloxypropyl. Optional substituents present on the Alk.sup.2 group include the R.sup.10 substituents described above.
When Alk.sup.1 is present in, or as a substituent R.sup.10, it may be, for example, a methylene, ethylene, n-propylene, i-propylene, n-butylene, i-butylene, s-butylene, t-butylene, ethenylene, 2-propenyl-ene, 2-butenylene, 3-butenylene, ethynylene, 2-propynylene, 2-butynylene or 3-butynylene chain, optionally interrupted by one, two, or three --O-- or --S-- atoms or --SO--, --SO.sub.2 -- or --N(R.sup.8)-- groups.
Particularly useful atoms or groups represented by R.sup.10 include fluorine, chlorine, bromine or iodine, C.sub.1-6 alkyl, for example, methyl or ethyl, C.sub.1-6 alkylamino, for example, methylamino or ethylamino, C.sub.1-6 hydroxyalkyl, for example, hydroxymethyl or hydroxyethyl, C.sub.1-6 alkylthiol, for example, methylthiol or ethylthiol, C.sub.1-6 alkoxy, for example, methoxy or ethoxy, C.sub.5-7 cycloalkoxy, for example, cyclopentyloxy, haloC.sub.1-6 alkyl, for example, trifluoromethyl, C.sub.1-6 alkylamino, for example, methylamino or ethylamino, amino (--NH.sub.2), aminoC.sub.1-6 alkyl, for example, aminomethyl or aminoethyl, C.sub.1-6 dialkylamino, for example, dimethylamino or diethylamino, nitro, cyano, hydroxyl (--OH), formyl [HC(.dbd.O)--], carboxyl (--CO.sub.2 H), --CO.sub.2 Alk.sup.2 [where Alk.sup.2 is as defined above], C.sub.1-6 alkanoyl, for example, acetyl, thiol (--SH), thioC.sub.1-6 alkyl, for example, thiomethyl or thioethyl, sulphonyl (--SO.sub.3 H), C.sub.1-6 alkylsulphonyl, for example, methylsulphonyl, aminosulphonyl (--SO.sub.2 NH.sub.2), C.sub.1-6 alkylaminosulphonyl, for example, methylaminosulphonyl or ethylaminosulphonyl, C.sub.1-6 dialkylaminosulphonyl, for example, dimethylaminosulphonyl or diethylaminosulphonyl, carboxamido (--CONH.sub.2), C.sub.1-6 alkylaminocarbonyl, for example, methylaminocarbonyl or ethyl-aminocarbonyl, C.sub.1-6 dialkylaminocarbonyl, for example, dimethylaminocarbonyl or diethylaminocarbonyl, sulphonylamino (--NHSO.sub.2 H), C.sub.1-6 alkylsulphonylamino, for example, methylsulphonylamino or ethylsulphonylamino, C.sub.1-6 dialkylsulphonylamino, for example, dimethylsulphonylamino or diethylsulphonylamino, aminosulphonylamino (--NHSO.sub.2 NH.sub.2), C.sub.1-6 alkylaminosulphonylamino, for example, methylaminosulphonylamino or ethylaminosulphonylamino, C.sub.1-6 dialkylaminosulphonylamino, for example, dimethylaminosulphonylamino or diethylaminosulphonylamino, C.sub.1-6 alkanoylamino, for example, acetylamino, C.sub.1-6 alkanoylaminoC.sub.1-6 alkyl, for example, acetylaminomethyl, or C.sub.1-6 alkoxycarbonylamino, for example, methoxycarbonylamino, ethoxycarbonylamino or t-butoxycarbonylamino.
Where desired, two R.sup.10 substituents may be linked together to form a cyclic group, such as a cyclic ether, for example, C.sub.2-6 alkylenedioxy, such as ethylenedioxy.
It will be appreciated that where two or more R.sup.10 substituents are present, their meanings in each instance is independent of the other, and they may be the same or different. The R.sup.10 substituents may be present at any ring carbon atom away from that attached to the rest of the molecule of formula (1). Thus, for example, in phenyl groups represented by At, any substituent may be present at the 2-, 3-, 4-, 5- or 6position relative to the ring carbon atom attached to the remainder of the molecule.
In the compounds of formula (1), when an ester group is present, for example, --CO.sub.2 Alk.sup.2, this may advantageously be a metabolically labile ester.
The presence of certain substituents in the compounds of formula (1) can enable salts of the present compounds to be formed. As known to those skilled in the art, it is generally preferred that, for biologically active materials to be useful as medicaments, they be available in a form which enables easy preparation of stable pharmaceutical formulations. For example, in certain cases, biologically active compounds contain at least one basic nitrogen atom and, therefore, are capable of existing in free base or salt form. However, the free base forms are often unsuitable for the ready preparation of stable pharmaceutical formulations and are often desirably converted to their corresponding salts. Thus, in the context of the present invention, suitable salts of the compounds described herein include pharmaceutically acceptable salts, for example, acid addition salts derived from inorganic or organic acids, and salts derived from inorganic and organic bases. It has been found that certain compounds of the present invention exhibit improved physical properties in salt form, and especially, acid addition salt form. Accordingly, these salts, which are discussed in detail below, comprise a preferred embodiment of the present invention.
Acid addition salts include, for example, hydrochlorides, hydrobromides, hydroiodides, alkylsulphonates, for example, methanesulphonates, ethanesulphonates or isethionates, arylsulphonates, for example, p-toluenesulphonates, besylates or napsylates, phosphates, sulphates, including hydrogen sulphates, acetates, trifluoroacetates, propionates, citrates, maleates, fumarates, malonates, succinates, lactates, oxalates, tartrates and benzoates.
Salts derived from inorganic or organic bases include alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts.
Particularly useful salts of compounds according to the invention include pharmaceutically acceptable salts, especially acid addition pharmaceutically acceptable salts. Preferred among the pharmaceutically acceptable acid addition salts are the sulphate salts, with hydrogen sulphate salts being particularly preferred. It has been found that hydrogen sulphate salts of the compounds of the present invention possess advantageous chemical and physical characteristics, relative, for example, to the free base and other salt forms. In particular, the hydrogen sulphate salts are characterized as being (1) highly crystalline; (2) thermally stable; (3) non-hygroscopic; and (4) soluble in aqueous solutions over a wide range of concentrations. In addition, hydrogen sulphate salts which are devoid of solvents and other impurities can be readily prepared. Due to these advantageous properties, the acid addition salts of the compounds of the present invention, and especially, the hydrogen sulfate salts, possess desirable preparation, handling, purity and stability characteristics.
In the compounds of formula (1), Y is preferably --OR.sup.1, for example, where R.sup.1 is substituted or unsubstituted methyl or ethyl, or, especially, substituted or unsubstituted methyl. Especially useful substituents which may be present on R.sup.1 include one, two or three fluorine or chlorine atoms.
X in the compounds of formula (1) is preferably --O--.
A particularly useful class of compounds of formula (1) has the formula (2): ##STR3## where R.sup.2 is substituted or unsubstituted cycloalkyl; R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are as defined for formula (1); and the salts, solvates, hydrates and N-oxides thereof.
In the compounds of formulae (1) or (2), R.sup.2 is preferably substituted unsubstituted methyl or cyclopentyl. More preferably, R.sup.2 is cyclopentyl.
R.sup.3 in the compounds of formulae (1) or (2) is preferably hydrogen.
In the compounds of formulae (1) or (2), R.sup.6 is preferably hydrogen or methyl, or especially hydrogen.
R.sup.7 in the compounds of formulae (1) or (2) is preferably hydrogen or methyl, or especially hydrogen.
In one preference, each of R.sup.6 and R.sup.7 in the compounds of formula (1) is methyl. In another preference, one of R.sup.6 and R.sup.7 is methyl and the other is hydrogen. In general, however, R.sup.6 and R.sup.7 is each especially hydrogen.
R.sup.4 and R.sup.5 in the compounds of formulae (1) or (2) is each, independently, preferably --CH.sub.2 Ar or, especially, --Ar.
Particularly useful R.sup.4 or R.sup.5 groups in the compounds of formulae (1) or (2) include those R.sup.4 or R.sup.5 groups in which Ar is a monocyclic aryl group, optionally containing one or more heteroatoms selected from oxygen, sulphur, or, in particular, nitrogen atoms, and optionally substituted by one, two, three or more R.sup.10 substituents. In these compounds, when Ar is heteroaryl, it is preferably nitrogen-containing monocyclic heteroaryl, especially six-membered nitrogen-containing heteroaryl. Thus, in one preferred example, R.sub.4 and R.sup.5 may each be six-membered nitrogen-containing heteroaryl. In another preferred example, R.sup.4 may be monocyclic aryl or monocyclic heteroaryl containing an oxygen or sulphur atom and R.sup.5 may be six-membered nitrogen-containing heteroaryl. In these examples, the six-membered nitrogen-containing heteroaryl group may be substituted or unsubstituted pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl. Particular examples include substituted or unsubstituted 2-pyridyl, 3-pyridyl or, especially, 4-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl or 3-pyrazinyl. The monocyclic aryl group may be phenyl or substituted phenyl, and the monocyclic heteroaryl group containing an oxygen or sulphur atom may be substituted or unsubstituted 2-furyl, 3-furyl, 2-thienyl or 3-thienyl.
One particularly useful class of compounds of formulae (1) or (2) is that wherein R.sup.4 and R.sup.5 is each pyridyl or, especially, monosubstituted pyridyl, or preferably disubstituted pyridyl, or R.sup.4 is phenyl, thienyl or furyl, or substituted phenyl, thienyl or furyl, and R.sup.5 is pyridyl or, especially monosubstituted pyridyl, or preferably disubstituted pyridyl.
In this particular class of compounds and also in general in compounds of formulae (1) or (2), when R.sup.4 and/or R.sup.5 is substituted phenyl, it may be, for example, a mono-, di- or trisubstituted phenyl group in which the substituent is R.sup.10 as defined above. When R.sup.4 and/or R.sup.5 is monosubstituted phenyl, the substituent may be in the 2-, or preferably the 3-, or especially the 4-position relative to the ring carbon atom attached to the remainder of the molecule.
When in compounds of formulae (1) or (2), R.sup.4 and/or R.sup.5 is substituted pyridyl, it may be, for example, mono- or disubstituted pyridyl, such as mono- or disubstituted 2-pyridyl, 3-pyridyl or especially 4-pyridyl substituted by one or two R.sup.10 substituents as defined above, and in particular one or two halogen atoms, such as fluorine or chlorine atoms, or methyl, methoxy, hydroxyl or nitro. Particularly useful pyridyl groups of these types are 3-monosubstituted-4-pyridyl or 3,5-disubstituted-4-pyridyl, or 2- or 4-monosubstituted-3-pyridyl or 2,4-disubstituted-3-pyridyl.
A particularly useful class of compounds according to the invention has the formula (2) wherein R.sup.3, R.sup.6 and R.sup.7 is each hydrogen and R.sup.2, R.sup.4 and R.sup.5 are as defined for formula (1); and the salts, solvates, hydrates and N-oxides thereof. Compounds of this type in which R.sup.2 is cycloalkyl or substituted cycloalkyl, especially substituted cyclopentyl, or in particular, cyclopentyl, are particularly useful. In this class of compounds, R.sup.4 is preferably monocyclic aryl, particularly phenyl or substituted phenyl, or R.sup.4 is a six-membered nitrogen-containing monocyclic heteroaryl group, particularly pyridyl or substituted pyridyl and R.sup.5 is a six-membered nitrogen-containing monocyclic heteroaryl group, especially pyridyl or substituted pyridyl, and in particular, substituted or unsubstituted 4-pyridyl.
Particularly useful compounds according to the invention are:
(.+-.)-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(2-furyl)ethyl]pyridine; PA0 (.+-.)-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(2-thienyl)ethyl]pyridine; PA0 (.+-.)-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]-3-methylimida zole; PA0 (.+-.)-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine; PA0 (.+-.)-4-[1-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl]pyridine; PA0 (.+-.)-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(4-fluorophenylethyl]pyrid ine; PA0 (.+-.)-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(4-trifluoromethylphenyl)e thyl]pyridine; PA0 (.+-.)-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(2-methoxyphenylethyl)]pyr idine; PA0 (.+-.)-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(4-methoxyphenyl) ethyl]pyridine; PA0 (.+-.)-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(4-methylphenyl)ethyl]pyri dine; PA0 (.+-.)-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(3-methylphenyl)ethyl]pyri dine; PA0 (.+-.)-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(3-cyclopentyloxy-4-methox yphenyl)-ethyl]pyridine; PA0 (.+-.)-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]-3, 5-dichloropyridine; PA0 (.+-.)-2-[2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine; PA0 (.+-.)-4-[1-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl]aniline; PA0 (.+-.)-4-[1-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl]benzoic acid; PA0 (.+-.)-Ethyl-N-{4-[1-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(4pyridyl)ethyl]p henyl}-carbamate; PA0 (.+-.)-N-{4-[1-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl]phenyl }-N'-ethylurea; PA0 (.+-.)-N-{4-[1-(3-Cyclopentyloxy-4-methoxyphenyl) ]-2-(4-pyridyl)ethyl}phenylacetamide; PA0 (.+-.)-3-[2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine; PA0 (.+-.)-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyrimidine; PA0 (.+-.)-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(4-hydroxymethylphenyl)eth yl]pyridine; PA0 (.+-.)-4-[1-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl]benzamide ; PA0 (.+-.)-Ethyl-4-[1-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(4-phenylethyl]benzo ate; PA0 (.+-.)-N-{4-[1-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl)phenyl }methane-sulphonamide; or
the resolved enantiomers thereof; and the salts, solvates, hydrates and N-oxides thereof.
The above specifically mentioned compounds exist in two enantiomeric forms. Each enantiomer is useful, as are mixtures of both enantiomers.
Compounds according to the invention, including the compounds defined generically by formula (1), as well as the compounds specifically listed above, are selective and potent inhibitors of PDE IV. The ability of the compounds to act in this way may be simply determined by the tests described in the Examples hereinafter.
In certain preferred embodiments of the present invention, the compound of formula (1) comprises the racemic mixture (.+-.)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2phenylethyl]-pyridine. An isomer contained in this mixture, (+)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine, is particularly preferred. The (+)-isomer of 4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine corresponds to the (R)-isomer and is, therefore, alternatively referred to herein as (R)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine.
As noted above, certain preferred embodiments of the present invention involve the salt forms, including the acid addition salt forms, such as the sulphate salts, with the hydrogen sulphate salt being particularly preferred. Especially preferred among the sulphate salts is (R)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine sulphate salt, with (R)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine hydrogen sulphate salt being particularly preferred.
The compounds according to the invention are thus of particular use in the prophylaxis and treatment of human diseases where an unwanted inflammatory response or muscular spasm including, for example, bladder or alimentary smooth muscle spasm, is present and where the elevation of cAMP levels may be expected to prevent or alleviate the inflammation and relax muscle.
Particular uses to which the compounds of the invention may be put include the prophylaxis and treatment of asthma, especially inflamed lung associated with asthma, or in the treatment of inflammatory airway disease, chronic bronchitis, eosinophilic granuloma, psoriasis and other benign and malignant proliferative skin diseases, endotoxic shock, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, inflammatory arthritis, chronic glomerulonephritis, atopic dermatitis, urticaria, allergic rhinitis, adult respiratory distress syndrome, diabetes insipidus, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis and artherosclerosis.
The compounds of the present invention can also suppress neurogenic inflammation through elevation of cAMP in sensory neurones. Thus, the present compounds can act as analgesic, antitussive and anti-hyperalgesic agents for the treatment of irritation and pain associated with inflammatory diseases.
Compounds according to the invention may also elevate cAMP in lymphocytes and thereby suppress unwanted lymphocyte activation in immune-based diseases, such as rheumatoid arthritis, rheumatoid spondylitis, transplant rejection and graft versus host disease. The present compounds have also been found to reduce gastric acid secretion and therefore can be used to treat conditions associated with hypersecretion.
Compounds according to the invention suppresses cytokine synthesis by inflammatory cells in response to immune or infectious stimulation. The compounds are, therefore, useful in the treatment of bacterial, fungal or viral induced sepsis and septic shock in which cytokines, such as tumor necrosis factor (TNF), are key mediators. Also, the present compounds suppress inflammation and pyrexia due to cytokines and are thus useful in the treatment of inflammation and cytokine-mediated chronic tissue degeneration which occurs in diseases such as rheumatoid or osteoarthritis.
Over-production of cytokines, such as TNF, in bacterial, fungal or viral infections or in diseases such as cancer, leads to cachexia and muscle wasting. The compounds of the present invention are capable of ameliorating these symptoms with a consequent enhancement of quality of life.
Compounds of the invention also elevate cAMP in certain areas of the brain and thereby counteract depression and memory impairment.
The present compounds can also suppress cell proliferation in certain tumor cells and can be used, therefore, to prevent tumor growth and invasion of normal tissues.
For the prophylaxis or treatment of disease, the compounds according to the invention may be administered as pharmaceutical compositions, and according to a further aspect of the invention, there is provided a pharmaceutical composition which comprises a compound of formula (1), or a pharmaceutically-acceptable salt thereof, together with one or more pharmaceutically-acceptable carriers, excipients or diluents.
Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration, or a form suitable for administration by inhalation or insufflation.
Advantageously, the pharmaceutical compositions may be prepared using conventional procedures. Thus, the invention further provides a process for the preparation of a pharmaceutical composition containing (R)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine hydrogen sulphate salt together with one or more pharmaceutically acceptable carriers, excipients or diluents which comprises the step or steps of combining (R)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine hydrogen sulphate salt with one or more pharmaceutically acceptable carriers, excipients or diluents.
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients, such as binding agents, for example, pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose; fillers, for example, lactose, microcrystalline cellulose or calcium hydrogen phosphate; lubricants, for example, magnesium stearate, talc or silica; disintegrants, for example, potato starch or sodium glycollate; or wetting agents, for example, sodium lauryl sulphate. The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives, such as suspending agents, emulsifying agents, non-aqueous vehicles and preservatives. The preparations may also contain buffer salts, flavoring, coloring and sweetening agents, as appropriate.
Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
For buccal administration the compositions may take the form of tablets or lozenges, formulated in a conventional manner.
The compounds of formula (1) may be formulated for parenteral administration by injection, for example, bolus injection or infusion. Formulations for injection may be presented in unit dosage form, for example, in glass ampule or multi-dose containers, such as glass vials. The compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents, such as suspending, stabilizing, preserving and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, for example, sterile pyrogen-free water, before use.
In addition to the formulations described above, the compounds of formula (1) may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or by intramuscular injection.
For nasal administration or administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation for pressurized packs or a nebulizer, with the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack or dispensing device may be accompanied by instructions for administration.
The quantity of a compound of the invention required for the prophylaxis or treatment of a particular inflammatory condition will vary depending, for example, on the compound chosen, and the condition of the patient to be treated. In general, however, daily dosages may range from about 100 ng/kg to about 100 mg/kg, for example, about 0.01 mg/kg to about 40 mg/kg body weight for oral or buccal administration, from about 10 ng/kg to about 50 mg/kg body weight for parenteral administration, and about 0.05 mg to about 1000 mg, for example, about 0.5 mg to about 1000 mg for nasal administration or administration by inhalation or insufflation.
The compounds according to the invention may be prepared by the following processes. The symbols Y, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and X, when used in the formulae below, are to be understood to represent those groups described above in relation to formula (1), unless otherwise indicated. In the reactions described below, it may be necessary to protect reactive functional groups, for example, hydroxy, amino, thio, or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the involved reactions. Conventional protecting groups may be used in accordance with standard practice [see, for example, Green, T. W., "Protective Groups in Organic Synthesis John Wiley and Sons, 1981.] Deprotection can take place in the last step in the synthesis of compounds of formula (1). Thus, for example, compounds of formula (1), wherein R.sup.4 and/or R.sup.5 contains a carboxylic acid group, may be prepared by deprotecting the corresponding compound wherein R.sup.4 and/or R.sup.5 contains a protected carboxyl group, such as an oxazolinyl group, for example, 4,4-dimethyl-2-oxazolinyl, in the presence of a base, for example, sodium hydroxide, in an acid solvent, for example, aqueous hydrochloric acid, at an elevated temperature, for example, the reflux temperature.
Thus, according to a further aspect of the invention, a compound of formula (1) wherein R.sup.3 and R.sup.7 is each a hydrogen atom may be prepared by hydrogenation of a compound of formula (3): ##STR4##
The hydrogenation may be performed using, for example, hydrogen in the presence of a catalyst. Suitable catalysts include metals, such as platinum or palladium, optionally supported on an inert carrier, such as carbon or calcium carbonate; nickel, for example, Raney nickel, or rhodium. The reaction may be performed in a suitable solvent, for example, an alcohol, such as methanol or ethanol, an ether, such as tetrahydrofuran or dioxane, or an ester, such as ethyl acetate, optionally in the presence of a base, for example, a tertiary organic base, such as triethylamine, at, for example, ambient temperature.
Alternatively, the reaction may be accomplished by transfer hydrogenation using an organic hydrogen donor and a transfer agent. Suitable hydrogen donors include, for example, acids, such as formic acid, formates, for example, ammonium formate, alcohols, such as benzyl alcohol or ethylene glycol, hydrazine, and cycloalkenes, such as cyclohexene or cyclohexadiene. The transfer agent may be, for example, a transition metal, for example, palladium or platinum, optionally supported on an inert carrier as discussed above, nickel, for example, Raney nickel, ruthenium, for example, tris(triphenylphosphine)ruthenium chloride, or copper. The reaction may generally be performed at an ambient or elevated temperature, optionally in the presence of a solvent, for example, an alcohol, such as ethanol, or an acid, such as acetic acid.
Intermediates of formula (3) may be prepared using a Horner-Wadsworth-Emmons approach by reaction of a ketone of formula (6) [described hereinafter] with phosphonate R.sup.5 CH.sub.2 PO(OAlk).sub.2, where Alk is C.sub.1-4 alkyl, such as methyl, in the presence of a base, such as sodium hydride. The phosphonates for use in this reaction may be prepared by conventional methods, for example, by reaction of a compound R.sup.5 CH.sub.2 L, where L is a leaving group, such as a chlorine atom, with a phosphine P(OAlk).sub.3.
In another process for the preparation of intermediates of formula (3), an alkene of formula (4): ##STR5## may be coupled in a Heck reaction with an organopalladium compound derived from a compound R.sup.5 Hal [where Hal is a halogen atom, such as a bromine atom] and a palladium salt, such as palladium acetate, in the presence of a phosphine, such as tri-o-tolyl phosphine, and a base, such as triethylamine, at an elevated temperature and pressure.
Intermediate alkenes of formula (4) may be obtained by reaction of a corresponding ketone of formula (6) (described hereinafter) using a Wittig reaction employing a phosphonium salt, such as methyltriphenylphosphonium bromide, in the presence of a base, such as n-butyllithium, and an inert solvent, such as tetrahydrofuran, at, for example, about 0.degree. C. to about ambient temperature.
Intermediates of formula (3) may also be prepared by dehydration of an alcohol of formula (5): ##STR6## using an acid- or base-catalyzed elimination.
Suitable acids include, for example, phosphoric or sulphonic acids, for example, 4-toluenesulphonic acid. The reaction may be performed in an inert organic solvent, for example, a hydrocarbon solvent, such as toluene, at an elevated temperature, for example, about the reflux temperature. Base-catalyzed elimination may be performed using, for example, trifluoroacetic anhydride, in the presence of an organic base, such as triethylamine, at a low temperature, for example, from about 0.degree. C. to about ambient temperature, in a solvent, such as dichloromethane or tetrahydrofuran.
In certain instances, the reaction conditions used may also cleave the group R.sup.2 in the starting material of formula (4) to yield an intermediate of formula (3) where R.sup.2 is hydrogen. Such compounds may be converted to the desired compound of formula (3) by reaction with a halide R.sup.2 Hal (where Hal is a halogen atom, such as a bromine or chlorine atom) as described hereinafter in connection with the preparation of compounds of formula (1) from the corresponding compounds where R.sup.2 is hydrogen.
It will be appreciated that the alcohols of formula (5) are compounds of the invention in which R.sup.3 is hydroxyl. Thus, according to a further aspect of the invention, a compound of formula (1), wherein R.sup.3 is hydroxyl and R.sup.7 is hydrogen, may be prepared by reaction of a ketone of formula (6): ##STR7## with an organometallic reagent R.sup.5 R.sup.6 CHZ, where Z is a metal atom.
Metal atoms represented by Z include, for example, lithium atoms.
The reaction may be performed in a solvent, such as an ether, for example, a cyclic ether, such as tetrahydrofuran, at a low temperature, for example, about -70.degree. C. to about ambient temperature. This reaction is particularly suitable for the preparation of compounds of formula (1) wherein R.sup.5 is an electron deficient group, such as a 2- or 4-pyridyl group.
Reagents R.sup.5 R.sup.6 CHZ are either known compounds or may be prepared, preferably in situ during the above process, by reaction of a compound AlkCH.sub.2 Z [where Alk is alkyl, such as n-propyl] with a compound R.sup.5 R.sup.6 CH.sub.2, where necessary, in the presence of a base, such as an amine, for example, diisopropylamine, using the above-mentioned conditions.
Ketones of formula (6) may be prepared by oxidation of a corresponding alcohol of formula (7): ##STR8## using an oxidizing agent, such as manganese dioxide, in a solvent, such as dichloromethane, at ambient temperature.
Alternatively, ketones of formula (6) may be prepared by reaction of a halide of formula (8): ##STR9## [where Hal is a halogen atom, such as a bromine or chlorine atom] by halogen-metal exchange with a base, such as n-butyllithium, followed by reaction with a nitrile R.sup.4 CN, an acid chloride R.sup.4 COCl or an ester R.sup.4 CO.sub.2 Alk (where Alk is alkyl, for example, methyl), in a solvent, such as tetrahydrofuran, at a low temperature, for example, about -70.degree. C., and subsequent treatment with an acid, such as hydrochloric acid at, for example, about -20.degree. C. to about ambient temperature.
Alcohols of formula (7) may be prepared by reaction of an aldehyde of formula (9): ##STR10## with an organometallic compound, such as an organolithium compound R.sup.4 Li, or a Grignard reagent R.sup.4 MgBr, in a solvent, such as tetrahydrofuran, at a low temperature, for example, about -55.degree. C. to about 0.degree. C.
Aldehydes of formula (9) may be prepared by alkylation of a corresponding compound of formula (10): ##STR11## using a compound R.sup.2 Hal [where Hal is as previously defined] using the reagents and conditions described hereinafter for the alkylation of intermediates of formula (18).
Intermediates of formula (10) are either known compounds or may be prepared from known starting materials by methods analogous to those used for the preparation of the known compounds.
Halides of formula (8) may be prepared by alkylation of a compound of formula (11): ##STR12## using the reagents and conditions discussed above in relation to the alkylation of aldehydes of formula (10).
Halides of formula (11), where X is --O--, may be prepared by oxidation of an aldehyde of formula (12): ##STR13## using an oxidizing agent, such as 3-chloroperoxybenzoic acid, in a halogenated hydrocarbon, such as chloroform, at a temperature of from about 0.degree. C. to about room temperature.
Aldehydes of formula (12) and halides of formula (11), where X is --S-- or --N(R.sup.8)--, are either known compounds or may be prepared from known starting materials by methods analogous to those used for the preparation of the known compounds.
In yet another process according to the invention, compounds of formula (1), wherein R.sup.3, R.sup.6 and R.sup.7 is each a hydrogen atom, may be prepared by decarboxylation of an acid of formula (13): ##STR14##
The reaction may be carried out by treatment of the compound of formula (13) with a base, for example, an inorganic base, such as a hydroxide, including sodium hydroxide, in a solvent, such as an alcohol, for example, ethanol, at an elevated temperature, for example, the reflux temperature, followed by acidification of the reaction mixture to a pH of about pH 4 to about pH 6 with an acid, such as an inorganic acid, for example, hydrochloric acid, at an elevated temperature, for example, the reflux temperature.
If desired, the acid of formula (13) may be generated in situ from the corresponding ester or nitrile using the above reaction conditions, or by initial treatment with an acid.
Intermediates of formula (13) may be prepared by reacting a compound of formula (14) ##STR15## [where R.sup.14 is an ester of an acid --CO.sub.2 H, for example, an alkyl ester, such as an ethyl ester, or --CN, with a Grignard reagent R.sup.4 MgBr, in the presence of a complexing agent, for example, a copper (I) bromide-dimethyl sulphide complex, or copper (I) chloride with an organolithium compound, for example, R.sup.4 Li, in a solvent, for example, tetrahydrofuran, at low temperature, for example, about -40.degree. C., followed by treatment with a base or an acid to yield the acid of formula (13), where R.sup.14 is --CO.sub.2 H. The Grignard and the lithium reagents are either known compounds or may be prepared in a manner similar to that used to synthesize the known compounds.
Compounds of formula (14) may be obtained by reacting an aldehyde of formula (9) with an ester or nitrile R.sup.5 CH.sub.2 R.sup.14 in an acid solvent, such as acetic acid, at an elevated temperature, for example, the reflux temperature, in the presence of a base, such as ammonium acetate.
In a further process according to the invention, a compound of formula (1), wherein R.sup.3, R.sup.6 and R.sup.7 is each hydrogen and R.sup.5 is heteroaryl, may be generally prepared by cyclization of a compound of formula (15): ##STR16## where R is carboxyl [--CO.sub.2 H] or a reactive derivative thereof, a nitrile [--CN] or an imine salt with a bifunctional reagent W.sup.1 R.sup.5a W.sup.2 and, where necessary, a compound R.sup.5b W.sup.3 [where W.sup.1, W.sup.2 and W.sup.3, which may be the same or different, is each a reactive functional group or a protected derivative thereof, and R.sup.5a and R.sup.5b are components of the heteroaryl group R.sup.5, such that when added together with W.sup.1, W.sup.2 and W.sup.3 to the group R in compounds of formula (15), the resulting group --RW.sup.1 R.sup.5a W.sup.2 or --RW.sup.1 R.sup.5a W.sup.2 R.sup.5b W.sup.3 constitutes the heteroaryl group R.sup.5 ].
Reactive derivatives of carboxylic acids for use in this reaction include acid halides, for example, acid chlorides, amides, including thioamides, or esters, including thioesters. Imine salts include, for example salts of formula -C(OAlk).dbd.NH.sub.2.sup.+ A.sup.-, where Alk is C.sub.1-4 alkyl and A.sup.- is a counterion, for example, a chloride ion.
In this general reaction, the reactive functional groups represented by W.sup.1, W.sup.2 or W.sup.3 may be any suitable carbon, nitrogen, sulphur or oxygen nucleophiles. Particular examples include simple nucleophiles, such as carbanions, including those generated by the coupling of an alkyl group with an organometallic compound, and amino, thiol and hydroxyl.
In general, the cyclization reaction will initially be performed in a solvent, for example, an inert solvent, such as a halocarbon, for example, dichloromethane, an ether, for example, a cyclic ether, such as tetrahydrofuran, or a hydrocarbon, for example, an aromatic hydrocarbon, such as toluene, from a low temperature, for example, about -70.degree. C. to about the reflux temperature, where necessary in the presence of a base or a thiation reagent, for example, Lawesson's reagent, followed, if necessary, by heating to an elevated temperature, for example, about the reflux temperature.
Thus, in one particular example, compounds of formula (1), wherein R.sup.3, R.sup.6 and R.sup.7 is each hydrogen and R.sup.5 is benzothiazolyl, benzoxazolyl or benzimidazolyl, may be prepared by reaction of a compound of formula (15), where R is an acid halide, for example, an acid chloride, with a reagent W.sup.1 R.sup.5a W.sup.2, which is 2-aminothiophenol, 2-hydroxyphenol, or 1,2diaminobenzene, respectively, in the presence of a base, for example, an organic amine, such as pyridine, in a solvent, for example, a halocarbon, such as dichloromethane, from about -70.degree. C. to about the reflux temperature.
In another example of the general cyclization process, a compound of formula (15), where R is an acid halide: as described above, may be reacted with a compound W.sup.1 R.sup.5a W.sup.2, which is a monoalkylmalonate, for example, ethyl hydrogen malonate, followed by reaction with a compound R.sup.5b W.sup.3, which is hydrazine, to give a compound of formula (1), wherein R.sup.3, R.sup.6 and R.sup.7 is each hydrogen and R.sup.5 is 5-hydroxypyrazolyl.
In another variation of the cyclization process, the halide of formula (15) may be reacted with a compound W.sup.1 R.sup.5a W.sup.2, which is BrMg(CH.sub.2).sub.3 [--O(CH.sub.2).sub.2 O--], followed by reaction in an acid solution with a compound R.sup.5b W.sup.3, which is methylamine, to yield a compound of formula (1), wherein R.sup.3, R.sup.6 and R.sup.7 is each hydrogen and R.sup.5 is N-methylpyrrole.
In a further example of the cyclization process, the halide of formula (15) may be reacted with a compound W.sup.1 R.sup.5a W.sup.2, which is H.sub.2 NNHCSNH.sub.2, in an aromatic hydrocarbon, such as toluene, at an elevated temperature, for example, about 150.degree. C., followed by treatment with a base, for example, an inorganic base, such as sodium bicarbonate, to give a compound of formula (1), wherein R.sup.3, R.sup.6 and R.sup.7 is each hydrogen and R.sup.5 is 1,2,4-triazolyl-5-thiolate.
Intermediate compounds of formula (15) are particularly useful and form a further aspect of the invention. Active derivatives of the acids of formula (15) and other compounds of formula (15), where R is a nitrile or an imine salt, may be prepared from the corresponding acids [where R is --CO.sub.2 H] using conventional procedures for converting carboxylic acids to such compounds, including, for example, as described in the Examples hereinafter.
Acids of formula (15) [where R is --CO.sub.2 H] may be prepared by hydrolyzing a diester of formula (16) ##STR17## where Alk is C.sub.1-4 alkyl, for example, ethyl, with a base, for example, sodium hydroxide, in a solvent, for example, dioxane, at an elevated temperature, for example, about the reflux temperature, followed by acidification at an elevated temperature.
Diesters of formula (16) may be prepared by reacting a diester of formula (17) ##STR18## with an organometallic reagent, such as a Grignard reagent, using the conditions described above for the preparation of alcohols of formula (1).
In another process according to the invention, a compound of formula (1) may be prepared by alkylation of a compound of formula (18): ##STR19## using a reagent R.sup.2 L, where L is a leaving group.
Leaving groups represented by L include halogen atoms, such as iodine or chlorine or bromine atoms, or sulphonyloxy groups, such as arylsulphonyloxy groups, for example, p-toluenesulphonyloxy.
The alkylation reaction may be carried out in the presence of a base, for example, an inorganic base, such as a carbonate, for example, caesium or potassium carbonate, an alkoxide, for example, potassium t-butoxide, or a hydride, for example, sodium hydride, in a dipolar aprotic solvent, such as an amide, for example, a substituted amide, such as dimethylformamide, or an ether, for example, a cyclic ether, such as tetrahydrofuran, at ambient temperature or above for example, about 40.degree. C. to about 50.degree. C.
Intermediates of formula (18) may be obtained from the corresponding protected compound of formula (19): ##STR20## wherein X.sup.1 is protected hydroxy, thio or amino using conventional procedures [see Green, T. W. ibid]. Thus, for example, where X is t-butyldimethylsilyloxy, the required hydroxyl group may be obtained by treatment of the protected intermediate with tetrabutylammonium fluoride. The protected intermediate of formula (18) may be prepared in an analogous manner to the compounds of formula (1) using the reactions described herein and appropriately protected intermediates.
Compounds of formula (17) may be prepared by condensing an aldehyde of formula (9) with a malonate, for example, diethylmalonate, if necessary in the presence of catalysts, for example, piperidine and acetic acid, in an inert solvent, for example, toluene, at elevated temperature, for example, about the reflux temperature.
Compounds of formula (1) may also be prepared by interconversion of other compounds of formula (1). Thus, for example, a group represented by R.sup.4 or R.sup.5 in the compounds of formula (1) may be substituted in the aryl or heteroaryl portions by any of the groups R.sup.10 by an appropriate substitution reaction using the corresponding unsubstituted compound of formula (1) and a nucleophile or electrophile containing R.sup.10.
In another example of an interconversion process, a compound of formula (1), wherein the aryl or heteroaryl group in R.sup.4 and/or R.sup.5 contains a --CH.sub.2 NH.sub.2 substituent, may be prepared by the reduction of a corresponding compound, wherein R.sup.4 and/or R.sup.5 contains a nitrile group, using, for example, a complex metal hydride, such as lithium aluminum hydride, in a solvent, such as an ether, for example, diethylether.
In a further example, a compound of formula (1), wherein the aryl or heteroaryl group in R.sup.4 and/or R.sup.5 contains an alkanoylamino or alkanoylaminoalkyl substituent, may be prepared by acylation of a corresponding compound, wherein R.sup.4 and/or R.sup.5 contains --NH.sub.2 or alkylamino, by reaction with an acyl halide in the presence of a base, such as a tertiary amine, for example, triethylamine, in a solvent, such as dichloromethane.
In yet another example of an interconversion process, compounds of formula (1), wherein R.sup.4 and/or R.sup.5 is substituted by an ester [CO.sub.2 Alk2], for example, an ethanoate, may be prepared by esterification of a corresponding compound wherein R.sup.4 and/or R.sup.5 contains a carboxylic acid, using an acid halide, such as an acid chloride, for example, acetyl chloride, in an alcohol, such as ethanol, at an elevated temperature, such as the reflux temperature.
Compounds of formula (1), wherein R.sup.4 and/or R.sup.5 is substituted with carboxyl (--CO.sub.2 H), may be prepared from the corresponding compound wherein R.sup.4 and/or R.sup.5 contains a formyl group which can be oxidized with an oxidizing agent, for example, potassium permanganate, in a solvent, such as an alcohol, for example, tert-butanol, at about ambient temperature.
In a further interconversion reaction, compounds of formula (1), wherein R.sup.4 and/or R.sup.5 is substituted by an aminoalkyl group, such as dimethylaminomethyl, may be prepared by reductive amination of a corresponding compound wherein R.sup.4 and/or R.sup.5 contains a formyl group, using an amine, for example, dimethylamine, in the presence of a reducing agent, for example, sodium cyanborohydride, if necessary in the presence of a catalyst, for example, ethanolic HCl, in a solvent, such as an alcohol, for example, methanol, at about ambient temperature.
In another example of an interconversion reaction, a compound of formula (1), wherein R.sup.4 and/or R.sup.5 is substituted by a formyl group, may be reduced to the corresponding alcohol, for example, where R.sup.4 and/or R.sup.5 contains a hydroxymethyl group, using a reducing agent, for example, sodium borohydride, in a solvent, such as an alcohol, for example, ethanol, at a temperature of from about 20.degree. C. to about ambient temperature. The resulting alcohol may then be converted to the corresponding alkoxy derivative, for example, methoxymethyl, by reaction with an alkyl halide or alkyl sulphonate using the methods and reagents described above for the alkylation of intermediates of formula (18).
In a further example of an interconversion process, compounds of formula (1), wherein R.sup.4 and/or R.sup.5 contains a carboxamido (--CONHR.sup.11) or an aminocarbonyl (--NHCOR.sup.11) group, may be prepared by reaction of the corresponding compound wherein R.sup.4 and/or R.sup.5 contains --CO.sub.2 H or --NH.sub.2, respectively, by reaction with a carbamate, such as isobutyl chloroformate or ethyl chloroformate, in the presence of a base, such as an amine, for example, triethylamine or N-methylmorpholine, in a solvent, such as dichloromethane, or a mixture of solvents, for example, tetrahydrofuran and dimethylformamide, at a temperature of from about -20.degree. C. to about room temperature.
In a still further interconversion reaction, compounds of formula (1), wherein R.sup.4 and/or R.sup.5 is substituted by --NHCONHR.sup.11, may be prepared by reacting a corresponding compound wherein R.sup.4 and/or R.sup.5 is substituted by amino (--NH.sub.2), with an isocyanate, for example, ethyl isocyanate, in a solvent, for example, dichloromethane, at about ambient temperature.
In another example of an interconversion process, compounds of formula (1), wherein R.sup.7 is alkyl, may be prepared by interconversion of a compound of formula (1), where R.sup.7 is hydrogen, by reaction with a compound R.sup.7 L, where L is a leaving group, for example, a halogen atom, such as chlorine, in the presence of a base, for example, lithium diisopropylamide, in a solvent, such as tetrahydrofuran, at low temperature, such as about 0.degree. C.
Compounds of formula (1), wherein R.sup.3 corresponds to OR.sup.9 where R.sup.9 is alkyl, alkoxyalkyl, formyl or alkanoyl, may be prepared in another example of an interconversion process by reaction of a compound of formula (1), where R.sup.3 is --OH, with a compound R.sup.9 L, where R.sup.9 is as defined above and L is a leaving group as described above, in a solvent, such as dichloromethane or tetrahydrofuran, in the presence of base, for example, triethylamine or potassium tert-butoxide, at about room temperature.
In a further interconversion process, compounds of formula (1), wherein R.sup.9 is carboxamido (--CONHR.sup.11) or thiocarboxamido (--CSNHR.sup.11), may be prepared by reaction of a compound of formula (1), wherein R.sup.3 is hydroxyl, with an isocyanate R.sup.11 NCO or an isothiocyanate R.sup.11 NCS, in a solvent, for example, chloroform, in the presence of a base, for example, diisopropylethylamine, at about ambient temperature. The isocyanate R.sup.11 NCO and isothiocyanate R.sup.11 NCS are known compounds and may be prepared in a conventional manner.
In a further example, a compound of formula (1), wherein R.sup.9 is CONR.sup.11 R.sup.12, may be prepared by reaction of a compound of formula (1), wherein R.sup.9 is CONHR.sup.11, with a reagent R.sup.12 L (where L is a leaving group as described above) in the presence of a base, for example, sodium hydride, in a solvent, such as tetrahydrofuran, at low temperature, for example, about 0.degree. C.
In another example, an isothiocyanate of formula (1), where R.sup.9 is --CSNR.sup.11 R.sup.12, may be prepared by reacting a compound of formula (1), wherein R.sup.9 is (--CONR.sup.11 R.sup.1 2), with a thiation reagent, such as Lawesson's Reagent, in an anhydrous solvent, for example, toluene, at elevated temperature, such as about the reflux temperature.
N-oxides of compounds of formula (1) may be prepared, for example, by oxidation of the corresponding nitrogen base using an oxidizing agent, such as hydrogen peroxide, in the presence of an acid, such as acetic acid, at an elevated temperature, for example, about 70.degree. C. to about 80.degree. C., or alternatively, by reaction with a peracid, such as peracetic acid, in a solvent, for example, dichloromethane, at about ambient temperature.
Salts of the compounds of formula (1) may be prepared by reaction of a compound of formula (1), as a salt or in the free acid or base form, or as a mixture of salt, free acid and/or free base forms, with a suitable acid or base, as appropriate, in a suitable solvent, for example, an organic solvent, including alcohols, such as ethanol or isopropyl alcohol, aromatic hydrocarbons, such as benzene and toluene, or ethers, such as diethyl ether and tetrahydrofuran, using conventional procedures. In general, the reaction for the preparation of a salt may be performed at about ambient temperature or at elevated temperatures, for example, up to about 50.degree. C.
A particular enantiomer of a compound of formula (1) can be produced from a corresponding mixture of enantiomers using any suitable conventional procedure for resolving enantiomers.
Thus, for example, diastereomeric derivatives, for example, salts, may be produced by reaction of a mixture of enantiomers of formula (1), for example, a racemate, and an appropriate chiral compound, for example, a chiral acid or base. Suitable chiral acids include, for example, tartaric acid and other tartrates, such as dibenzoyl tartrates and ditoluoyl tartrates, sulphonates, such as camphor sulphonates, mandelic acid and other mandelates and phosphates, such as 1,1'-binaphthalene-2,2'-diyl hydrogen phosphate. The diastereomers may be separated by any convenient means, for example, by crystallization, and the desired enantiomer recovered, for example, by treatment with an acid or base when the diastereomer is a salt.
In another resolution process, a racemate of formula (1) may be separated using chiral High Performance Liquid Chromatography, for example, as described in the Examples hereinafter.
Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above. Thus, for example, a particularly useful method for preparing the individual enantiomers of Examples 15 and 16 involves the initial reaction of an ester of formula (14) with a base, followed by reaction with thionyl chloride and a camphor derivative, such as (+)-exo-10,2-bornanesultam or (-)-endo-10,2-bornanesultam [Aldrich Chem. Co.], followed by reaction of the resulting acyl sultam with a Grignard reagent as described above for the conversion of intermediates of formula (14) to intermediates of formula (13). The resulting intermediate acyl sultam may then be cleaved to the corresponding thioester using a thiol, such as ethane thiol, in a base and the thioester then treated to yield the desired enantiomer of formula (1) using the reactions and conditions described above for the conversion of intermediates of formula (13) to compounds of the invention. This overall process is described in detail in copending U.S. application Ser. No. 08/361,439, filed Dec. 21, 1994 and United Kingdom patent application 9326173.3, filed Dec. 22, 1993, the disclosures of each of which are hereby incorporated by reference herein, in their entirety.